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Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):E3901-10. doi: 10.1073/pnas.1523512113. Epub 2016 Jun 13.

OX40L blockade protects against inflammation-driven fibrosis.

Author information

1
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France; Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France;
2
Department of Rheumatology, Oslo University Hospital, 0873 Oslo, Norway;
3
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
4
Equipe d'Accueil (EA) 2496 Pathologie, Imagerie et Biothérapies Orofaciales, Faculty of Odontology, Paris Descartes University, Sorbonne Paris Cite, 92120 Montrouge, France; Plateforme d'Imagerie Du Vivant, Le Pôle de Recherche et d'Enseignement Supérieur Sorbonne Paris Cité, 92120 Montrouge, France;
5
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;
6
Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Helmholtz Zentrum München, DE-81377 Munich, Germany; Institute for Immunology, Ludwig-Maximilians-Universität München, DE-80336 Munich, Germany;
7
Immune Mediated Diseases, Sanofi Genzyme, Framingham, MA 01701;
8
Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France;
9
INSERM, U1173, Faculty of Health Sciences Simone Veil, Université Versailles-Saint-Quentin, 78180 Saint-Quentin-En-Yvelines, France.
10
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France; Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France; yannick.allanore@cch.aphp.fr.

Abstract

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

KEYWORDS:

OX40L; costimulation; fibrosis; systemic sclerosis; translational approach

PMID:
27298374
PMCID:
PMC4941508
DOI:
10.1073/pnas.1523512113
[Indexed for MEDLINE]
Free PMC Article

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